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The manifestation of Weyl fermions in strongly correlated electron systems is of particular interest. We report evidence for Weyl fermions in the heavy fermion semimetal YbPtBi from electronic structure calculations, angle-resolved photoemission spectroscopy, magnetotransport and calorimetric measurements. At elevated temperatures where 4f-electrons are localized, there are triply degenerate points, yielding Weyl nodes in applied magnetic fields. These are revealed by a contribution from the chiral anomaly in the magnetotransport, which at low temperatures becomes negligible due to the influence of electronic correlations. Instead, Weyl fermions are inferred from the topological Hall effect, which provides evidence for a Berry curvature, and a cubic temperature dependence of the specific heat, as expected from the linear dispersion near the Weyl nodes. The results suggest that YbPtBi is a Weyl heavy fermion semimetal, where the Kondo interaction renormalizes the bands hosting Weyl points. These findings open up an opportunity to explore the interplay between topology and strong electronic correlations.

Abstract Eco-friendly Sn-based perovskites show significant potential for high-performance second near-infrared window light-emitting diodes (900 nm – 1700 nm). Nevertheless, achieving efficient and stable Sn-based perovskite second near-infrared window light-emitting diodes remains challenging due to the propensity of Sn2+ to oxidize, resulting in detrimental Sn4+-induced defects and compromised device performance. Here, we present a targeted strategy to eliminate Sn4+-induced defects through moisture-triggered hydrolysis of tin tetrahalide, without degrading Sn2+ in the CsSnI3 film. During the moisture treatment, tin tetrahalide is selectively hydrolyzed to Sn(OH)4, which provides sustained protection. As a result, we successfully fabricate second near-infrared window light-emitting diodes emitting at 945 nm, achieving a performance breakthrough with an external quantum efficiency of 7.6% and an operational lifetime reaching 82.6 h.

Abstract Tumor heterogeneity and tumor evolution contribute to cancer treatment failure. To understand how selective pressures drive heterogeneous tumor evolution, it would be useful to image multiple important components and tumor subclones in vivo. We propose a supercontinuum-tailoring two-photon microscope (SCT-TPM) and realize simultaneous observation of nine fluorophores with a single light beam, breaking through the ‘color barrier’ of intravital two-photon fluorescence imaging. It achieves excitation multiplexing only by modulating the phase of fiber supercontinuum (SC), allowing to capture rapid events of multiple targets with maintaining precise spatial alignment. We employ SCT-TPM to visualize the spatiotemporal dynamics of heterogeneous tumor evolution under host immune surveillance, particularly the behaviors and interactions of six tumor subclones, immune cells and vascular network, and thus infer the trajectories of tumor progression and clonal competition. SCT-TPM opens up the possibility of tumor lineage tracking and mechanism exploration in living biological systems.

Abstract The Challenger Deep (CD) is the deepest known hadal trench in the world. Due to challenges in data sampling at extreme ocean depths, the Lower Circumpolar Deep Water (LCDW) transport and ocean circulation structure in the CD remain unclear. By analyzing data from an extra-deep current meter mooring array, here we find a three-layer circulation in the CD, transitioning downward from westward LCDW flow (about −1.866 ± 2.953 Sv, 1 Sv = 106 m3/s) to cyclonic circulation, and then to anticyclonic circulation. The westward flow reverses its direction during summer, giving evidence for bidirectional connectivity of deep-sea basins, while the cyclonic-anticyclonic circulation is relatively steady. The LCDW intrusion, local topography and turbulent mixing are crucial for modulating the three-layer circulation. Turbulent mixing plays a key role in driving the anticyclonic circulation. Our findings provide insights for understanding the hydrodynamic environment in the ocean’s deepest areas.

Abstract The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves’ disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Abstract Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes.

Abstract Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson’s (STAB1, KCNA10), Alzheimer’s (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson’s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Abstract The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Abstract Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

Abstract Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Superconductivity in the cuprates is found to be intertwined with charge and spin density waves. Determining the interactions between the different types of order is crucial for understanding these important materials. Here, we elucidate the role of the charge density wave (CDW) in the prototypical cuprate La1.885Sr0.115CuO4, by studying the effects of large magnetic fields (H) up to 24 Tesla. At low temperatures (T), the observed CDW peaks reveal two distinct regions in the material: a majority phase with short-range CDW coexisting with superconductivity, and a minority phase with longer-range CDW coexisting with static spin density wave (SDW). With increasing magnetic field, the CDW first grows smoothly in a manner similar to the SDW. However, at high fields we discover a sudden increase in the CDW amplitude upon entering the vortex-liquid state. Our results signify strong coupling of the CDW to mobile superconducting vortices and link enhanced CDW amplitude with local superconducting pairing across the H − T phase diagram. Superconductivity in the cuprates is known to be intertwined with charge and spin density waves. Here, the authors study the prototypical cuprate La1.885Sr0.115CuO4 via x-ray scattering and discover a sudden increase in the charge-density-wave amplitude upon entering the superconducting-vortex-liquid state at high magnetic field. [ABSTRACT FROM AUTHOR]

Abstract Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.

Abstract The pathogenesis of thyroid dysgenesis (TD) is not well understood. Here, using a combination of single-cell RNA and spatial transcriptome sequencing, we identify a subgroup of NF-κB-activated thyrocytes located at the center of thyroid tissues in postnatal mice, which maintained a partially mesenchymal phenotype. These cells actively protruded out of the thyroid primordium and generated new follicles in zebrafish embryos through continuous tracing. Suppressing NF-κB signaling affected thyrocyte migration and follicle formation, leading to a TD-like phenotype in both mice and zebrafish. Interestingly, during thyroid folliculogenesis, myeloid cells played a crucial role in promoting thyrocyte migration by maintaining close contact and secreting TNF-α. We found that cebpa mutant zebrafish, in which all myeloid cells were depleted, exhibited thyrocyte migration defects. Taken together, our results suggest that myeloid-derived TNF-α-induced NF-κB activation plays a critical role in promoting the migration of vertebrate thyrocytes for follicle generation.

Abstract Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

Abstract Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily oscillations in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

Abstract The limited sensitivity of photovoltaic-type photodiodes makes it indispensable to use pre-amplifier circuits for effectively extracting electrical signals, especially when detecting dim light. Additionally, the photomultiplication photodiodes with light amplification function suffer from potential damages caused by high power consumption under strong light. In this work, by adopting the synergy strategy of thermal-induced interfacial structural traps and blocking layers, we develop a dual-mode visible-near infrared organic photodiode with bias-switchable photomultiplication and photovoltaic operating modes, exhibiting high specific detectivity (~1012 Jones) and fast response speed (0.05/3.03 ms for photomultiplication-mode; 8.64/11.14 μs for photovoltaic-mode). The device also delivers disparate external quantum efficiency in two optional operating modes, showing potential in simultaneously detecting dim and strong light ranging from ~10−9 to 10−1 W cm−2. The general strategy and working mechanism are validated in different organic layers. This work offers an attractive option to develop bias-switchable multi-mode organic photodetectors for various application scenarios.

Abstract Constructing 2D/3D perovskite heterojunctions is effective for the surface passivation of perovskite solar cells (PSCs). However, previous reports that studying perovskite post-treatment only physically deposits 2D perovskite on the 3D perovskite, and the bulk 3D perovskite remains defective. Herein, we propose Cl2-dissolved chloroform as a multifunctional solvent for concurrently constructing 2D/3D perovskite heterojunction and inducing the secondary growth of the bulk grains. The mechanism of how Cl2 affects the performance of PSCs is clarified. Specifically, the dissolved Cl2 reacts with the 3D perovskite, leading to Cl/I ionic exchange and Ostwald ripening of the bulk grains. The generated Cl− further diffuses to passivate the bulk crystal and buried interface of PSCs. Hexylammonium bromide dissolved in the solvent reacts with the residual PbI2 to form 2D/3D heterojunctions on the surface. As a result, we achieved high-performance PSCs with a champion efficiency of 24.21% and substantially improved thermal, ambient, and operational stability.

Abstract Physical reservoirs holding intrinsic nonlinearity, high dimensionality, and memory effects have attracted considerable interest regarding solving complex tasks efficiently. Particularly, spintronic and strain-mediated electronic physical reservoirs are appealing due to their high speed, multi-parameter fusion and low power consumption. Here, we experimentally realize a skyrmion-enhanced strain-mediated physical reservoir in a multiferroic heterostructure of Pt/Co/Gd multilayers on (001)-oriented 0.7PbMg1/3Nb2/3O3−0.3PbTiO3 (PMN-PT). The enhancement is coming from the fusion of magnetic skyrmions and electro resistivity tuned by strain simultaneously. The functionality of the strain-mediated RC system is successfully achieved via a sequential waveform classification task with the recognition rate of 99.3% for the last waveform, and a Mackey-Glass time series prediction task with normalized root mean square error (NRMSE) of 0.2 for a 20-step prediction. Our work lays the foundations for low-power neuromorphic computing systems with magneto-electro-ferroelastic tunability, representing a further step towards developing future strain-mediated spintronic applications.

Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.

Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.

Perovskite structure is disturbed by environmental moisture, limiting the device performance. Here, Wei et al. monitor the effect of moisture during the growth by N2-protected characterization techniques, and obtain an operationally stable perovskite solar cell with efficiency approaching 24%.

Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis.

Vitrification from physical vapor deposition is known to be an efficient way for tuning the kinetic and thermodynamic stability of glasses and significantly improve their properties. There is a general consensus that preparing stable glasses requires the use of high substrate temperatures close to the glass transition one, Tg. Here, we challenge this empirical rule by showing the formation of Zr-based ultrastable metallic glasses (MGs) at room temperature, i.e., with a substrate temperature of only 0.43Tg. By carefully controlling the deposition rate, we can improve the stability of the obtained glasses to higher values. In contrast to conventional quenched glasses, the ultrastable MGs exhibit a large increase of Tg of ∼60 K, stronger resistance against crystallization, and more homogeneous structure with less order at longer distances. Our study circumvents the limitation of substrate temperature for developing ultrastable glasses, and provides deeper insight into glasses stability and their surface dynamics. [ABSTRACT FROM AUTHOR]

Stability of zeolite catalysts is a highly desirable property for commercial methanol to olefins conversion but extremely challenging to achieve. Here, the authors combine the catalyst pre-coking and water co-feeding to develop an efficient strategy to enhance the long-term stability of SAPO-34 catalyst.

Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.